Disrupting Mechanisms that Regulate Genomic Repeat Elements to Combat Cancer and Drug Resistance.

Despite advancements in understanding cancer pathogenesis and the development of many effective therapeutic agents, resistance to drug treatment remains a widespread challenge that substantially limits curative outcomes. The historical focus on genetic evolution under drug "pressure" as a key driver of resistance has uncovered numerous mechanisms of therapeutic value, especially with respect to acquired resistance. However, recent discoveries have also revealed a potential role for an ancient evolutionary balance between endogenous "viral" elements in the human genome and diverse factors involved in their restriction in tumor evolution and drug resistance. It has long been appreciated that the stability of genomic repeats such as telomeres and centromeres affect tumor fitness, but recent findings suggest that de-regulation of other repetitive genome elements, including retrotransposons, might also be exploited as cancer therapy. This review aims to present an overview of these recent findings.

Therapy-induced senescence promotes breast cancer cells plasticity by inducing Lipocalin-2 expression.

The acquisition of novel detrimental cellular properties following exposure to cytotoxic drugs leads to aggressive and metastatic tumors that often translates into an incurable disease. While the bulk of the primary tumor is eliminated upon exposure to chemotherapeutic treatment, residual cancer cells and non-transformed cells within the host can engage a stable cell cycle exit program named senescence. Senescent cells secrete a distinct set of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Upon exposure to the SASP, cancer cells undergo cellular plasticity resulting in increased proliferation, migration and epithelial-to-mesenchymal transition. The molecular mechanisms by which the SASP regulates these pro-tumorigenic features are poorly understood. Here, we report that breast cancer cells exposed to the SASP strongly upregulate Lipocalin-2 (LCN2). Furthermore, we demonstrate that LCN2 is critical for SASP-induced increased migration in breast cancer cells, and its inactivation potentiates the response to chemotherapeutic treatment in mouse models of breast cancer. Finally, we show that neoadjuvant chemotherapy treatment leads to LCN2 upregulation in residual human breast tumors, and correlates with worse overall survival. These findings provide the foundation for targeting LCN2 as an adjuvant therapeutic approach to prevent the emergence of aggressive tumors following chemotherapy.

Pro- and anti-tumorigenic functions of the senescence-associated secretory phenotype.

Introduction: Cellular senescence is a stable form of cell cycle exit. Though they no longer divide, senescent cells remain metabolically active and secrete a plethora of proteins collectively termed the senescence-associated secretory phenotype (SASP). Although senescence-associated cell cycle exit likely evolved as an anti-tumor mechanism, the SASP contains both anti- and pro-tumorigenic potential.Areas covered: In this review, we briefly discuss the discovery of senescent cells and its relationship to cancer and aging. We also describe the initiation and regulation of the SASP upon senescence stimulus onset. We focus on both the pro- and anti-tumorigenic properties of the SASP. Finally, we speculate on the potential benefits of therapy-induced senescence combined with selective SASP inhibition for the treatment of cancer.Expert opinion: Further identification and characterization of the SASP factors that are pro-tumorigenic and those that are anti-tumorigenic in specific contexts will be crucial in order to develop personalized therapeutics for the successful treatment of cancer.

Uncoupling the Senescence-Associated Secretory Phenotype from Cell Cycle Exit via Interleukin-1 Inactivation Unveils Its Protumorigenic Role.

Cellular senescence has emerged as a potent tumor suppressor mechanism in numerous human neoplasias. Senescent cells secrete a distinct set of factors, collectively termed the senescence-associated secretory phenotype (SASP), which has been postulated to carry both pro- and antitumorigenic properties depending on tissue context. However, the in vivo effect of the SASP is poorly understood due to the difficulty of studying the SASP independently of other senescence-associated phenotypes. Here, we report that disruption of the interleukin-1 (IL-1) pathway completely uncouples the SASP from other senescence-associated phenotypes such as cell cycle exit. Transcriptome profiling of IL-1 receptor (IL-1R)-depleted senescent cells indicates that IL-1 controls the late arm of the senescence secretome, which consists of proinflammatory cytokines induced by NF-κB. Our data suggest that both IL-1α and IL-1ß signal through IL-1R to upregulate the SASP in a cooperative manner. Finally, we show that IL-1α inactivation impairs tumor progression and immune cell infiltration without affecting cell cycle arrest in a mouse model of pancreatic cancer, highlighting the protumorigenic property of the IL-1-dependent SASP in this context. These findings provide novel insight into the therapeutic potential of targeting the IL-1 pathway in inflammatory cancers.

NAD+ metabolism governs the proinflammatory senescence-associated secretome.

Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.

Senescence Phenotypes Induced by Ras in Primary Cells.

Cellular senescence is defined as a state of stable cell-cycle arrest that is distinct from quiescence and terminal differentiation. Many stimuli can induce senescence, including telomere shortening and oncogene activation. The phenotypes elicited by pro-senescent signals can be heterogeneous depending on the stimulus and the cell type affected. To date, there is not a definitive marker that can ubiquitously and specifically mark all senescent cells. Therefore, several independent markers must be utilized to ascertain the senescent state of a cell or group of cells. Here, we describe common assays used to assess oncogenic Ras-induced senescence.